Prediction of outcome in locally advanced breast cancer by post-chemotherapy nodal status and baseline serum tumour markers.

In spite of the apparent improvement in outcome in locally advanced breast cancer, the prognosis remains dismal in many patients. The aim of this study was to define prognostic subgroups within this heterogeneous entity. Between 1990 and 1999, 104 consecutive patients with locally advanced breast cancer were treated by a multimodality programme consisting of 4-6 courses of CAF induction chemotherapy followed by surgery, breast-conserving when feasible. In most cases, chemotherapy was then resumed, up to a total of eight courses, followed by locoregional radiation therapy. Patients with hormone receptor-positive tumours received tamoxifen (20 mg day(-1)) for 5 years. At a median follow-up of 57 months, the 5-year overall survival for the entire group and the disease-free survival for the 94 operated patients were 65% and 53%, respectively. Univariate analysis identified 10 prognostic factors of overall and disease-free survival, of which four retained significance on multivariate analysis: inflammatory breast cancer (P=0.0000, P=0.0004, respectively), baseline tumour markers (P=0.003 for both), post-chemotherapy number of involved nodes (P=0.003; P=0.017) and extracapsular spread (P=0.052; P=0.014). In conclusion, besides inflammatory features, baseline tumour markers and post-chemotherapy nodal status are strong predictors of outcome in locally advanced breast cancer.

[Letrozole (Femara), a new aromatase inhibitor for advanced breast cancer]. / Letrozol (Femara), novyi ingibitor aromatazy dlia lecheniia bol'nykh rasprostranennym rakom molochnoi zhelezy.

The study compares letrozole (Femara and aminoglutethimide (AG), a standard therapy for postmenopausal women with advanced breast cancer, previously treated with anti-estrogens. 555 women were randomly assigned letrozole 2.5 mg once daily (n = 185), letrozole 0.5 mg once daily (n = 192) or aminoglutethimide 250 mg twice daily with corticosteroid support (n = 178) in an open-label, multicenter trial. The primary end-point was objective response rate (ORR), with time events as secondary. ORR was analysed nine months after enrollment of the last patient, while survival was analysed 15 months after the last patients was enrolled. We report the results of these analyses plus an extended period of observation (covering a total duration of approximately 45 months) to determine the duration of response and clinical benefit. Overall objective response rates (complete + partial) of 19.5%, 16.7% and 12.4% were seen for letrozole 2.5 mg, 0.5 mg and AG respectively. Median duration of response and stable disease was longest for letrozole 2.5 mg (21 months) compared with letrozole 0.5 mg (18 months) and AG (14 months). Letrozole 2.5 mg was superior to AG in time to progression, time to treatment failure and overall survival. Treatment-related adverse events occurred in fewer patients on letrozole (33%) than on AG (46%). Letrozole 2.5 mg offers longer disease control than aminoglutethimide and letrozole 0.5 mg in the treatment of postmenopausal women with advanced breast cancer, previously treated with anti-estrogens.

Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3).

BACKGROUND: The study compares letrozole and aminoglutethimide (AG), a standard therapy for postmenopausal women with advanced breast cancer, previously treated with antioestrogens. PATIENTS AND METHODS: 555 women were randomly assigned letrozole 2.5 mg once daily (n = 185), letrozole 0.5 mg once daily (n = 192) or aminoglutethimide 250 mg twice daily with corticosteroid support (n = 178) in an open-label, multicentre trial. The primary endpoint was objective response rate (ORR), with time events as secondary. ORR was analysed nine months after enrollment of the last patient, while survival was analysed 15 months after the last patient was enrolled. We report the results of these analyses plus an extended period of observation (covering a total duration of approximately 45 months) to determine the duration of response and clinical benefit. RESULTS: Overall objective response rates (complete + partial) of 19.5%, 16.7% and 12.4% were seen for letrozole 2.5 mg, 0.5 mg and AG respectively. Median duration of response and stable disease was longest for letrozole 2.5 mg (21 months) compared with letrozole 0.5 mg (18 months) and AG (14 months). Letrozole 2.5 mg was superior to AG in time to progression, time to treatment failure and overall survival. Treatment-related adverse events occurred in fewer patients on letrozole (33%) than on AG (46%). Transient nausea was the most frequent event with letrozole (7% on 0.5 mg, 10% on 2.5 mg, 10% on AG), rash with AG (11%, 1% on 0.5 mg, 3% on 2.5 mg letrozole). CONCLUSIONS: Letrozole 2.5 mg offers longer disease control than aminoglutethimide and letrozole 0.5 mg in the treatment of postmenopausal women with advanced breast cancer, previously treated with anti-oestrogens.

The effect of irradiation on expression of HLA class I antigens in human brain tumors in culture.

The immunosuppressive effects of irradiation are well known; however, under certain circumstances irradiation also augments the local immune response by as yet undefined mechanisms. Because of the importance of HLA class I antigen in immune regulation and the fact that killing of tumor cells by cytotoxic T cells is HLA antigen-restricted, the authors studied HLA class I antigen expression in eight glioblastomas multiforme, four meningiomas, and four medulloblastomas. Twenty fragments of each tumor specimen were placed in short-term cultures immediately after resection. For each tumor, control Sample 1 was not irradiated. Sample 2 was irradiated on Day 1, and two groups of the remaining pieces of each tumor (specimens 3 to 10) were irradiated on two consecutive days. Escalating radiation doses were given, starting at 200 cGy/day for Sample 2 up to 1000 cGy/day for Sample 10. The total dose range was 200 to 2000 cGy. Corresponding nonirradiated tumor fragments served as controls. Four hours after irradiation, each sample was processed and stained for HLA class I antigen using the immunoperoxidase technique. The tumor cells were intensely stained in nonirradiated glioblastomas and meningiomas, whereas no staining was observed in medulloblastomas. In four of the eight glioblastomas and in all four meningiomas, irradiation augmented HLA class I antigen expression compared to controls. This effect was dose-dependent and was maximum in the 1200 cGy-treated specimens. No change was observed in the other four glioblastomas or in the medulloblastomas. The data suggest that irradiation does not decrease and may even induce HLA class I antigen expression in some brain tumors. This may be one of the mechanisms by which immunotherapy operates after irradiation. Further studies are required to elucidate optimum radiation doses and fractionation as well as optimum timing of immunotherapy.

Elevated pretreatment levels of soluble CD8 and Beta-2-microglobulin as indicators of relapse in breast-cancer patients.

We measured soluble CD8 ((S)CD8) and microglobulin (beta-2M) in 128 breast cancer patients and in 200 controls by the ELISA method. Patient groups were: Group A-new patients; Group B-patients on follow-up; Group C-patients with metastases. The mean (S)CD8 and beta-2M were significantly higher in patients than in controls ((S)CD8 p<0.01, beta-2M p<0.0001). Both for (S)CD8 and beta-2M, groups A and C had high levels which differed significantly from Group B ((S)CD8 p<0.04; beta-2M p<0.0001). A significant correlation between (S)CD8 and B-2M was observed (r=0.379: p=0.0001). Twenty patients relapsed. In 14/20 (70%) an initial high (S)CD8 and in 10/20 (50%), high beta-2M was observed. High initial CD8 and beta-2M were able to identify 80% of relapsed patients. High (S)CD8 and beta-2M levels are indicative of tumor bulk and are able to identify patients at.

Serum intracellular adhesion molecule-1 (sicam-1) and soluble hla class-1 antigens in breast-cancer patients in relation to tumor burden.

sICAM-1 and beta-2 microglobulin (beta-2M) serum levels were measured in 143 breast cancer patients and 43 controls. The patients were divided into three groups. A: new patients; B: patients on long term follow-up and C: metastatic patients. In all patients the mean +/-1SD sICAM-1 and beta-2M serum levels were significantly higher than normal controls (p <0.001 and p <0.0001, respectively). Analysis of the three groups showed that for both sICAM-1 and beta-2M, Groups A and C had similar serum levels, which differed significantly from Group B. sICAM-1 of Group B was similar to controls, while beta-2M of Group B was significantly higher than controls. During the study 20 patients relapsed. Initial high levels of sICAM-1 were observed in 20% and beta-2M in 50% of patients. These data suggest that sICAM-1 and beta-2M level indicate host cell-mediated immunity against tumor.

The treatment of advanced Merkel cell carcinoma. A multimodality chemotherapy and radiation therapy treatment approach.

BACKGROUND: The optimal management of Merkel cell carcinoma has not been clearly defined. OBJECTIVE: To describe the treatment of eight patients who presented with Merkel cell carcinoma. METHODS: Eight patients with advanced locoregional Merkel cell carcinoma were seen in our institute over a 7-year period. Four patients were successfully treated by induction chemotherapy after excisional biopsy, followed by radiotherapy. Three patients died from widespread metastases and one from neutropenic sepsis induced by chemotherapy. RESULTS: These cases demonstrate the potential lethality and aggressive nature of this rare skin tumor despite its chemosensitive and radioresponsive character. In all four patients who are alive and disease-free, chemotherapy was given first and radiotherapy was given as consolidation. CONCLUSION: We suggest that a multimodality treatment approach--chemotherapy followed by radiotherapy--is indicated in patients with advanced Merkel cell carcinoma.

The use of cyclophosphamide, methotrexate, and 5-fluorouracil in the treatment of Merkel cell carcinoma.

Five patients with advanced Merkel cell carcinoma (MCC) are described. Four patients with regional lymph node involvement and one with disseminated skin metastases were treated with systemic chemotherapy, including cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). The patients received a median of six cycles of CMF (range: 2 to 6), and chemotherapy was well tolerated. Four complete and one partial response were noted. Three patients are alive and are disease-free at 5, 12, and 37 months from the onset of CMF chemotherapy. Two patients died from disseminated metastatic disease at 3 and 24 months from the onset of chemotherapy. CMF chemotherapy appears to be an active regimen in the treatment of locally advanced MCC. Further experience with this combination is warranted.

Quantitative and qualitative assessment of plasma von Willebrand factor in classic Kaposi's sarcoma.

BACKGROUND: von Willebrand factor (vWF) is synthesized almost exclusively by endothelial cells and is stored there as ultra-high-molecular-weight multimers. The vWF multimers that are detected in the plasma are smaller than those stored within the endothelium. In two previous studies, comprising small series of cases with classic Kaposi's sarcoma (KS), an endothelium-derived tumor, increased levels of plasma von Willebrand factor antigen (VWF:Ag, the antigenic structure) were reported, suggesting that vWF:Ag may be a marker of endothelium proliferation. OBJECTIVE: Our purpose was to investigate the quantitative as well as qualitative alterations of plasma vWF in a large series of patients with classic KS at various stages of the disease. METHODS: Levels of plasma vWF:Ag were studied in 38 patients with classic KS confined to the skin at various stages of the disease and compared with a control group. Thirty-three patients had active KS (i.e., with skin lesions) and five were in remission. In five patients with active KS multimeric analysis of plasma vWF was also performed. RESULTS: The levels of vWF:Ag were significantly higher among KS patients than in the control group (n = 29, p < 0.01). Levels of vWF:Ag were also significantly higher in patients with active disease as compared with those in remission (p < 0.05). No correlation was found between vWF:Ag levels and the extent of KS. Analysis of the multimeric pattern of plasma vWF showed enhanced staining of all bands, particularly the intermediate and high molecular weight forms, which resemble the endothelial forms as opposed to normal circulating vWF multimers. CONCLUSION: Quantitative as well as qualitative alterations in plasma vWF were found in patients with KS, which may reflect the destruction or activation of endothelial cells within the lesions. vWF:Ag may serve as a marker of disease activity in classic KS; however, it is not a good marker for the extent of the disease.

Amplification of the expression of major histocompatibility class-I antigens by inducers of differentiation and gamma interferon in murine and human solid tumor-cell lines.

Treatment of B16 F10-9 mouse melanoma cell line and RC-29 human renal carcinoma cell line with chemical inducers of differentiation such as sodium butyrate (SB) hexamethylene bisacetamide (HMBA) and L-histidinol significantly increased the expression of major histocompatability complex (MHC) class I antigens. This effect depends on the continued exposure of the cells to these materials. Combined treatment of the B16 F10-9 melanoma cells with recombinant murine gamma interferon and SB increased the expression of MHC class I antigens in a synergistic manner. This effect of chemical inducers of differentiation might be of importance in rendering tumor cells more sensitive to the immune defense mechanisms.

Prognostic factors in node-positive operable breast cancer patients receiving adjuvant chemotherapy.

A retrospective analysis of prognostic factors in 214 consecutive node-positive (N+) operable breast cancer patients, receiving Melphalan + 5-fluorouracil adjuvant chemotherapy between 1980 and 1984 was performed. Median follow-up was 95 months. Actuarial disease-free interval (DFI) and survival (S) were determined according to age, menopausal status, histology, size of primary tumor (T), multifocality, tumor location, hormonal receptor status, number of N+, size of N+, tumor spread in axillary fat, and interval between surgery and onset of adjuvant chemotherapy. On univariate analysis two factors were prognostic for DFI and S: number of N+ and T size. A comparison between traditionally classified T1 and T2 patients revealed no significant difference, but when the cut-off point was shifted from 2 cm to 3 cm, T size represented a highly significant prognostic factor. In patients with T less than or equal to 3 cm 5-year DFI was 54% and 5-year S was 76%, while in patients with T greater than 3 cm the respective values were 23% (p less than 0.001) and 41% (p less than 0.001). These significant DFI and S differences persisted after adjustment for number of N+ by bivariate analysis. Multivariate analysis supported the importance of T greater than 3 cm as a strong adverse predictor. Four adverse variables, T greater than 3 cm, number of N+ greater than or equal to 4, multifocality, and tumor spread in axillary fat were used to divide our patients into three subsets with significantly different DFI: Group I, with none of the above factors; Group II, with only one factor present; and Group III, with more than one factor present (5 years DFI 66%, 45%, and 21%, respectively; p less than 0.001).

The controversial treatment of anterior commissure carcinoma of the larynx.

There are two basic approaches to the appropriate therapy for carcinoma of the anterior commissure. The dilemma of whether to treat by primary irradiation or by conservative surgery is not yet solved. In this study, 67 patients were treated between 1967 and 1987 for anterior commissure carcinoma of the larynx. Radiation was used with 47 patients and conservation surgery with 20 patients. Initial lesion control was achieved with 72% of the patients treated by primary irradiation. Conservation surgery, when used as a primary treatment modality, achieved local control in 90% of the patients. The new techniques of reconstruction of the larynx enhance the surgeon's ability, strengthen his conviction to proceed to enlarged partial laryngectomies, and thus improve the oncologic control of the anterior commissure carcinoma as well.

Hereditary ovarian cancer: a dilemma in prognosis.

Five women in three generations developed ovarian cancer. We closely monitored 36 descendent women in this family who were at high risk for developing this disease. Prophylactic oophorectomy is considered the optimal way to prevent the development of ovarian cancer. In the light of the young age of the women at risk and their strong objection to oophorectomy, we closely monitored the examinees for early signs of cancer for more than 5 years. None of them developed cancer. The dilemma in treatment of women at risk is discussed.

Does mca contribute to the follow-up of breast-cancer patients by ca-15-3.

Mucin-like carcinoma-associated antigen (MCA) and CA 15-3 tumor markers were randomly assayed in 234 consecutive breast cancer patients. It was found that 45 patients (19.2%) had elevated MCA levels (cut-off level >14 U/ml) and normal CA 15-3 levels (cut off level >30 U/ml). In 14 of these 45 patients (31.1%), overt metastases were detected, although five had started their follow-up with no evidence of disease. In these five patients, the median lead time was nine months. In our limited experience, it was found that measuring MCA levels in the serum in the presence of normal CA15-3 levels contributes to early detection and monitoring of recurrences in follow-up of breast cancer patients.

Circumscribed scleroderma induced by postlumpectomy radiation therapy.

A 57-year-old woman who had undergone a lumpectomy for infiltrating duct cell carcinoma of the right breast was found to have morphea after receiving radiation therapy. The morphea occurred at the site of the irradiated field. It is suggested that the irradiation served as a provoking factor and that the morphea might be an isomorphic response to the trauma of the irradiation.

Soluble histocompatibility antigen class I in breast cancer patients in relation to tumor burden.

Serum beta-2 microglobulin (B-2M) levels were studied in 365 breast cancer patients and 210 age-matched controls. The patients were divided into three groups: Group A, new patients at diagnosis; Group B, patients at follow-up; and Group C, metastatic patients. The mean B-2M of all breast cancer patients plus or minus one standard deviation (3.5 +/- 1.2; range, 1.1 to 5.9) was significantly higher than normal controls (1.29 +/- 0.49; range, 0.3 to 2.3; P less than 0.005). When the three patient groups were compared with each other, the mean B-2M level of Group A (3.0 +/- 1.5; range, 0.9 to 6.9) was similar to that of Group C (4.22 +/- 1.1; range, 2.0 to 6.4). The mean B-2M of both Groups A and C was significantly higher than that of Group B (2.38 +/- 1.02, range, 0.4 to 5.4; P less than 0.001). In Group A the mean B-2M decreased significantly after a 12-month period and reached the mean level of Group B but not that of normal controls. When patients in Group B were analyzed by their stage of disease at diagnosis, there was no significant difference between Stages I and II. There was a significant difference in the mean B-2M levels between Stages I and III. In relapsing patients, mean B-2M levels increased. These findings suggest that serum B-2M levels may reflect tumor burden, and even in patients at follow-up, occult tumor cells may activate the immune system.

Expression of HLA class I and class II in gastric carcinoma in relation to pathologic stage.

The expression of HLA class I and II antigens was studied in 41 patients with gastric cancer and in 2 normal stomachs. The normal gastric epithelia were diffusely stained for class I antigens. No staining was observed for class II. In gastric cancer an overall reduction in staining was observed, which was related to the degree of tumor penetration through the gastric wall. In tumors which penetrated the mucosa and submucosa only, 80-90% of tumor cells were stained for class I, as well as the normal areas surrounding the tumor. On the other hand, in tumors which penetrated through the organ to the fat, only 10-20% of cells were stained. Staining for class II was observed in only 12 cases, all of them advanced, with penetration to muscle or fat. No staining was observed in the normal areas surrounding the tumor. The importance of HLA antigens in immune surveillance is discussed.

A clinical evaluation of nuclear estrogen receptors combined with cytosolic estrogen and progesterone receptors in breast cancer.

Breast cancer tissue from 95 women was simultaneously assayed for three receptors: cytosolic estrogen (CER), cytosolic progesterone (CPR), and nuclear estrogen (NER). The main objective was to determine whether the addition of NER assay to the currently accepted practice with only CER and CPR could improve the predictive capacity of receptors. Forty-two patients were studied for response to hormone therapy and 95 patients were studied for survival; the median follow-up period was 73 months (range, 8 to 300 months). The incidence of CER+, CPR+, and NER+ was 74%, 70%, and 52%, respectively. Each receptor appeared more frequently, although not significantly so, in higher age groups. Forty percent of tumors had all three receptors positive and 14% had all negative; the remaining tumors showed all possible combinations of receptors. Both the rate of response and survival curves among 70 patients with CER+ did not show any significant difference whether NER was positive or negative. Also, among 38 patients with CER+, CPR+, and NER+, there was no significant difference in the clinical outcome as compared to 17 patients with CER+, CPR+, and NER-. Among 25 patients with CER- the rare occurrence of NER+ in only three patients did not suggest any clinical implication. It is concluded, therefore, that on overall clinical grounds the current series does not support the addition of NER assay whenever data is available on both CER and CPR.

[Prognostic factors in multiple myeloma].

There have been major advances in the treatment of multiple myeloma in the past 20 years, but for the individual patient the prognosis still remains uncertain. As the length of survival varies from several months to over 10 years, definition of prognostic parameters at the time of diagnosis, and early detection of disease activity are most important. In our study, median survival was 42 months with very good quality of life. Factors not helpful in prognosis were sex, WBC and platelet counts, BUN, serum M protein type, extent of osteolytic lesions, percentage of plasma cells in bone marrow and plasma cell asynchrony. However, age, hemoglobin, calcium, uric acid, Bence-Jones proteinuria and polyclonal Ig concentrations had a certain degree of prognostic importance. Due to more sensitive and more specific laboratory methods, peripheral blood findings are lately gaining in importance. With new "salvage" protocols, the detection of additional prognostic parameters and sensitive indicators of disease activity may be most important for further improvement in the survival of patients with multiple myeloma.